Project Summary Influenza virus (INFV) results in global seasonal and pandemic outbreaks estimated to cause severe illness in 3 to 5 million people annually resulting in significant morbidity and up to 650,000 deaths. The influenza burden also results in substantial economic loss. The goal of this program is to develop a therapeutic antibody offering effective treatment with broad heterosubtypic specificity for influenza viruses without inducing resistance. Our therapeutic antibody (3I14) has shown broad neutralizing activity against 14 strains of INFV A Groups 1 and 2 and both prophylactic and therapeutic protection in BALB/c mouse models of H1, H3, H5 and H7 serotypes. This Fast-track proposal is intended to establish a stable expressing cell line for manufacturing, identify an optimal product formulation, characterize the dose response and tolerability of the product in nonclinical studies, and complete the mouse efficacy data package. Completion of these milestones are critical for advancement to IND-enabling studies and clinical development. 3I14 binds the stem of both the uncleaved HA precursor and two mature forms of HA, either after trypsin activation alone or when followed by low-pH trigger. 3I14 prevents both the dissociation of HA1-HA2 and the pH-dependent HA rearrangement necessary for membrane fusion. Targeting the highly conserved HA stem epitope is also expected to drastically reduce the likelihood of viral resistance, a significant barrier to developing effective therapeutics for influenza. Integrated Biotherapeutics (IBT) has extensive experience in preclinical model and antibody product development for infectious diseases. Dr. Holtsberg and his team have extensive experience in providing services to pharma companies over the past 8 years in the development and use of in vitro assays and animal models for testing influenza therapies. This expertise is complimented by a strong strategic partnership with AbViro LLC with subject matter expertise specific to influenza and focus on integrated program management skillsets, extensive knowledge of preclinical product development and clinical science, regulatory expertise, and business and commercialization strategy for broad-spectrum antibodies capable of advancing 3I14 into clinical studies. IBT will also collaborate with MassBiologics, IIT Research Institute (IITRI) and La Jolla Institute for Allergy and Immunology (LJI). MassBiologics offers strong competency in stable cell line and manufacturing process development. IIT Research Institute (IITRI) provides relevant highly pathogenic influenza strains and animal models essential for rigorous evaluation of product efficacy. LJI provides core research functionality with next-generation sequencing capabilities. This development team has successfully advanced another broad-spectrum human monoclonal antibody targeting dengue virus to IND-enabling studies.